PROJECT ABSTRACT: Oncogenes and tumor suppressors directly highjack the cell?s translation apparatus to make their own tailored proteome to direct specific steps in cancer development. This is molecularly achieved through translationally regulated nodes of gene expression that can direct cancer initiation and progression. My lab has been at the forefront of this research by generating modern tools and developing the first genetic loss- and gain-of-function mouse models for distinct components of the translation machinery which, in combination with new quantitative measures of the translational landscape of gene regulation, have led to a fundamental change in our understanding regarding the molecular origins of cancer. In this proposal, we will leverage and extend our long-standing interests in translational control in cancer to address three major goals, as follows: 1) What are the synthetic lethal interactions targeting the aberrant translation control program in cancer? Here, we will characterize a series of novel synthetic lethal genetic interactions with the major cap-binding protein eIF4E that we have discovered specific to cancer cells. For example, we will elucidate a surprising genetic interaction between translational control and splicing as well as translation and mitochondrial proteostasis. We will translate these findings to in-vivo mouse models as well as xenografts and patient-derived xenografts to define the importance of such synthetic lethal interactions in human cancers and target them by employing new selective compounds that block eIF4E hyperactivation in human cancers. 2) How is translation control linked to metabolic programs in cancer cells? As nutrient abundance drives anabolic processes, such as protein synthesis, we will determine how translation control influences metabolic homeostasis linked to diet and the cellular environment in cancer. We will assess the functional consequences of genetically and pharmacologically modulating eIF4E activity in cancers associated with obesity and employ unbiased profiling methods to delineate the impact of eIF4E on metabolic signaling that circulates in the blood stream. 3) What are the mechanisms by which oncogenes direct the formation of ?cancer ribosomes?? A fundamentally unanswered question is whether the presence of distinct ?cancer ribosomes? may drive translation of the cancer genome to direct specific steps in cancer development. We will establish the first systematic, and large-scale characterization of ribosome composition and study its genome-wide impact on gene regulation during distinct phases in Myc-induced tumor development. Importantly, changes in ribosome composition may offer a completely new therapeutic pipeline to selectively inhibit human ribosomes that translate specific, cancer-causing mRNAs.